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Columbia, MO, United States

Crim M.J.,University of Missouri | Riley L.K.,IDEXX RADIL
ILAR Journal | Year: 2012

Naturally occurring viral infections have the potential to introduce confounding variability that leads to invalid and misinterpreted data. Whereas the viral diseases of research rodents are well characterized and closely monitored, no naturally occurring viral infections have been characterized for the laboratory zebrafish (Danio rerio), an increasingly important biomedical research model. Despite the ignorance about naturally occurring zebrafish viruses, zebrafish mod-els are rapidly expanding in areas of biomedical research where the confounding effects of unknown infectious agents present a serious concern. In addition, many zebrafish research colonies remain linked to the ornamental (pet) zebrafish trade, which can contribute to the introduction of new patho-gens into research colonies, whereas mice used for research are purpose bred, with no introduction of new mice from the pet industry. Identification, characterization, and monitoring of naturally occurring viruses in zebrafish are crucial to the improvement of zebrafish health, the reduction of unwanted variability, and the continued development of the zebrafish as a model organism. This article addresses the importance of identifying and characterizing the viral diseases of zebrafish as the scope of zebrafish models expands into new research areas and also briefly addresses zebrafish susceptibility to experimental viral infection and the utility of the zebrafish as an infection and immunology model. Source


Adams V.,University of Missouri | Myles M.H.,IDEXX RADIL
Journal of the American Association for Laboratory Animal Science | Year: 2013

Commercially available diagnostic tools for the detection of lactate dehydrogenase elevating virus (LDV) infection have been restricted to measurement of serum lactate dehydrogenase (LDH) activity levels and detection of the viral genome by RT-PCR assays. Serologic diagnosis of LDV infection has not been widely adopted due to the belief that the formation of antigen-antibody complexes and B-cell polyclonal activation may confound interpretation of results. In the current study, we inoculated BALB/c, C57BL/6, and Swiss Webster mice with LDV to compare the diagnostic reliability of a commercially available multiplex fluorescent immunoassay for the detection of antiLDV antibodies with that of the LDH enzyme assay. The serologic assay was vastly more sensitive and specific than was the LDH enzyme assay. Moreover, the serologic assay detected antiviral antibodies throughout the 3-mo time course of this study. These results suggest that antigen-antibody complex formation and polyclonal B-cell activation had little effect on assay performance. Copyright 2013 by the American Association for Laboratory Animal Science. Source


McCoy A.,Sigma-Aldrich | Besch-Williford C.L.,IDEXX RADIL | Franklin C.L.,University of Missouri | Weinstein E.J.,Sigma-Aldrich | Cui X.,Sigma-Aldrich
DMM Disease Models and Mechanisms | Year: 2013

The tumor suppressor TP53 plays a crucial role in cancer biology, and the TP53 gene is the most mutated gene in human cancer. Trp53 knockout mouse models have been widely used in cancer etiology studies and in search for a cure of cancer with some limitations that other model organisms might help overcome. Via pronuclear microinjection of zinc finger nucleases (ZFNs), we created a Tp53 knockout rat that contains an 11-bp deletion in exon 3, resulting in a frameshift and premature terminations in the open reading frame. In cohorts of 25 homozygous (Tp53Δ11/Δ11), 37 heterozygous (Tp53 Δ11/+) and 30 wild-type rats, the Tp53 Δ11/Δ11 rats lived an average of 126 days before death or removal from study because of clinical signs of abnormality or formation of tumors. Half of Tp53Δ11/+ were removed from study by 1 year of age because of tumor formation. Both Tp53Δ11/+ and Tp53 Δ11/Δ11 rats developed a wide spectrum of tumors, most commonly sarcomas. Interestingly, there was a strikingly high incidence of brain lesions, especially in Tp53Δ11/Δ11 animals. We believe that this mutant rat line will be useful in studying cancer types rarely observed in mice and in carcinogenicity assays for drug development. Source


Carroll C.E.,University of Missouri | Liang Y.,University of Missouri | Benakanakere I.,University of Missouri | Besch-Williford C.,IDEXX RADIL | Hyder S.M.,University of Missouri
International Journal of Oncology | Year: 2013

Recent epidemiological studies show that postmenopausal women taking estrogen-progestin hormone replacement therapy (HRT) have a higher risk of breast cancer than women on an HRT regimen lacking progestins. This may be related to the observation that progestin-treated breast cancer cells express and secrete high levels of vascular endothelial growth factor (VEGF), a potent angiogenic factor that promotes breast tumor growth. Anti-progestins such as RU-486 block this effect, indicating that progesterone receptors (PR) are involved in promoting VEGF induction; however antiprogestins cross-react with other steroid receptors which limits their clinical use. Alternative strategies are, therefore, needed to arrest the growth of progestin-dependent tumors. 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), a novel anticancer drug initially developed as an inhibitor of HIF-1α, is currently undergoing preclinical trials against various forms of cancer. Since HIF-1α has recently been implicated in PR-mediated VEGF synthesis, we undertook studies to determine whether YC-1 inhibits progestin-dependent VEGF induction and tumor progression. Surprisingly, we found that YC-1 downregulated PR in human breast cancer cells, both in vivo and in vitro, thereby blocking progestin-dependent induction of VEGF and tumor growth. YC-1 also inhibited progestin-accelerated DMBA-induced mammary tumors in rats, properties which would likely render it effective against progestin-dependent tumors which frequently develop in post-menopausal women. We, therefore, propose that based on our observations, YC-1 warrants further investigation as a novel agent which could prove extremely useful as an anti-angiogenic chemotherapeutic drug. Source


Yang F.,California Institute of Technology | Nickols N.G.,California Institute of Technology | Nickols N.G.,University of California at Los Angeles | Li B.C.,California Institute of Technology | And 5 more authors.
Journal of Medicinal Chemistry | Year: 2013

A hairpin pyrrole-imidazole polyamide (1) targeted to the androgen receptor consensus half-site was found to exert antitumor effects against prostate cancer xenografts. A previous animal study showed that 1, which has a chiral amine at the α-position of the γ-aminobutyric acid turn (γ-turn), did not exhibit toxicity at doses less than 10 mg/kg. In the same study, a polyamide with an acetamide at the β-position of the γ-turn resulted in animal morbidity at 2.3 mg/kg. To identify structural motifs that cause animal toxicity, we synthesized polyamides 1-4 with variations at the α- and β-positions in the γ-turn. Weight loss, histopathology, and serum chemistry were analyzed in mice post-treatment. While serum concentration was similar for all four polyamides after injection, dose-limiting liver toxicity was only observed for three polyamides. Polyamide 3, with an α-acetamide, caused no significant evidence of rodent toxicity and retains activity against LNCaP xenografts. © 2013 American Chemical Society. Source

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